This invention lies in the technology of transdermal and topical drug delivery. In particular, the present invention relates to enhancement of the penetration of transdermally or topically applied drugs and to reduction of the skin irritation that often accompanies transdermally and topically applied drug delivery.
During the past decade, the feasibility of the dermal route for systemic drug delivery has been established. Transdermal therapeutic systems include those containing scopolamine, glyceryl trinitrate, clonidine, fentanyl, nicotine and estradiol. However, one drawback with drugs applied to the skin or mucous membrane is that they frequently cause irritation. Additionally, many of the necessary components of topical, transdermal, and transmucosal formulations and delivery devices, such as solubilizing agents, suspending agents, dispersing agents, preservatives, animal and vegetable fats, oils, or waxes, stabilizing agents, thickening or gelling agents, buffering agents, adhesive agents, and, particularly, penetration enhancing agents, are irritating alone or in combination. However, in the absence of penetration enhancing agents, few drugs are capable of penetrating the skin or mucous membranes in therapeutically effective concentrations. Typically, using penetration enhancing compounds, processes or devices to increase drug penetration solves this problem. Included among these are chemical enhancers, iontophoresis, sonophoresis, and various delivery devices.
In most instances, penetration enhancement usually results in unwanted irritation. Many transdermal and topical products show high incidences of adverse skin reactions such as scaling, pruritic erythema, and vesicobollous irritant and allergic contact dermatitis. This is particularly true for topical and transdermal testosterone products currently on the market. Formulations comprised of combinations of ingredients of the same type instead of only one ingredient of that type, such as using a combination of two solvents instead of just one solvent, have been reported to lessen irritation without lowering drug permeation. This approach has also been applied to penetration enhancing agents. In particular, the use of glycerol, polyglycerol ethers, or dexpanthenol in combination with other penetration enhancing agents has been reported to lessen irritation. Using mixtures of penetration enhancers of different polarities and modes of action has also been reported to increase drug permeability without necessitating the use of higher concentrations of irritating penetration enhancers. The problem has also been approached by the additional inclusion of non-irritating ingredients such as glycerin.
U.S. Pat. No. 5,760,096, which issued to Thornfeldt et al. on Jun. 2, 1998, discloses a penetration enhancing system based on the use of various combinations of known penetration enhancing excipients. One type of penetration system disclosed combines an alcohol and a glycol, at glycol: alcohol weight ratios of about 1:0.1 to about 1:10, with one or more excipients categorized as surfactants, branched chain fatty acid esters, or membrane fluidizers.
In addition, U.S. Pat. No. 4,863,970, which issued to Patel et al. on Sep. 5, 1989, discloses a penetration-enhancing binary mixture of a cell-envelope-disordering compound and a lower alcohol. The binary mixtures can optionally contain inert ingredients that are soluble within the enhancer compositions. Neither Thornfeldt et al. nor Patel et al. teach or disclose the beneficial use of oleic acid in favor of oleyl alcohol. In addition, the use of a gelling agent in combination with oleic acid is not disclosed.
Ultimately, the success of transdermal systems depends on the ability of the drug to permeate the skin in sufficient quantities to achieve the desired therapeutic effect. However, the transdermal system""s ability for skin permeation is tempered by the irritation side effect that it can cause. There is a need in the art for a transdermal therapeutic system that has good penetration, but that has little unwanted skin and mucous membrane irritation. The present invention fulfills this and other needs.
The compositions of the present invention relate to a penetration enhancing system (PES) that can be utilized in many types of products for topical or transdermal application, that include, but are not limited to, solutions, creams, lotions, ointments, gels, aerosols and patch devices. In certain aspects, the present invention relates to a composition for topical application having penetration-enhancing properties, the composition comprising an active agent; and a penetration-enhancing system that comprises oleic acid; a C1-C4 alcohol; and a glycol. Optionally, the composition further comprises a gelling agent. In preferred embodiments, the gelling agent is CARBOPOL(copyright) which is a polyacrylic acid. In certain embodiments, the preferred active ingredient is testosterone or a testosterone derivative.
The penetration enhancing system of the present invention effectively enhances delivery of transdermally and/or topically active substances, while surprisingly reducing skin irritation caused by the application of irritating substances to the skin. The penetration enhancing system of the present invention can also be used for mucosal delivery.
In another aspect, the present invention relates to a method for administering a topically or systemically active agent, the method comprising: topically administering to a mammal a composition comprising: a) an active agent; and b) a penetration-enhancing system comprising: (i) oleic acid; (ii) a C1-C4 alcohol; and (iii) a glycol. Optionally, the penetration-enhancing system further comprises (iv) a gelling agent. In certain preferred embodiments, the method relates to treatment of conditions related to testosterone deficiency.
In yet another aspect, the present invention relates to a method of reducing inflammation associated with topical application of an active agent, the method comprising: topically administering to a terrestrial mammal a composition comprising: a) an active agent; and b) a penetration-enhancing system comprising: (i) oleic acid; (ii) a C1-C4 alcohol; and (iii) a glycol. In certain embodiments, the penetration-enhancing system further comprises (iv) a gelling agent. Typically, the inflammation is associated with the skin.
Further combinations, compositions and aspects of the present invention will be apparent with the following detailed description.